Medicament for use in a method of inducing or extending a cellular cytotoxic immune response

Abstract

The present invention relates to a medicament for use in a method of inducing a cellular cytotoxic immune response, the method comprising the steps of: i) administering to a patient a delivery system comprising (a) a molecule binding to a receptor on the surface of a dendritic cell, (b) an antigen-comprising protein bound to molecule of (a) and (c) a first adjuvant, wherein upon binding of the molecule of (a) to the receptor, the protein of (b) is internalized and processed in the dendritic cell and the antigen comprised in the protein is presented on the surface of the dendritic cell, thereby activating a T cell in the patient; and ii) administering to the patient a re-activator selected from the group consisting of (d) complexed interleukin 2 (IL-2cx), (e) a peptide-loaded major histocompatibility complex class I (MHC-I) presenting cell and a second adjuvant, and (f) a combination of (d) and (e), wherein the peptide is derived from the antigen-comprising protein as defined in step i), thereby reactivating the T cell activated in step i), wherein the re-activator of step ii) is administered in a time frame of from 0 h to 14 days after the administration of the delivery system of step i).

The invention claimed is: 
     
       1. A method of inducing amplification of antigen-specific CD8+ T cells in a patient, the method comprising the steps of:
 i) administering to the patient a delivery system comprising:
 (a) a molecule that binds to a XCR1, CLEC9A, nectin-like molecule 2, or CD205 receptor on the surface of a cross-presenting XCR1+ dendritic cell, wherein the molecule is a soluble protein ligand to the XCR1 receptor or an antibody or antigen-binding fragment thereof that binds the XCR1, CLEC9A, nectin-like molecule 2, or CD205 receptor; 
 (b) an antigen-comprising protein bound to the molecule of (a); and 
 (c) a first adjuvant which supports a Th-1 mediated response, wherein the first adjuvant is a danger signal, and wherein upon binding of the molecule of (a) to the receptor, the protein of (b) is internalized and processed in the dendritic cell and the antigen comprised in the protein is presented on the surface of the dendritic cell, thereby activating CD8+ T cells in the patient; and 
 
 ii) amplifying the CD8+ T cells activated in step i) by administering to the patient a re-activator comprising:
 (d) primary peptide-loaded major histocompatibility complex class I (MHC-I) presenting cells, wherein the MHC-I presenting cells comprise peripheral blood mononuclear cells (PBMCs) excluding monocyte-derived dendritic cells and wherein the MHC-I presenting cells are obtained from the patient and loaded in vitro with a peptide derived from the antigen-comprising protein of step i) prior to administration to the patient; 
 (e) a second adjuvant which supports a Th-1 mediated response, wherein the second adjuvant is a danger signal; and 
 (f) complexed interleukin 2 (IL-2cx), wherein the IL-2cx comprises IL-2 non-covalently bound to an antibody or fragment thereof, wherein the antibody or fragment thereof blocks the binding of IL-2 to the high affinity IL-2 receptor chain (CD25); 
 
 wherein each of (d), (e), and (f) of the re-activator of step ii) is administered in a time frame of from 5 days to 12 days after the administration of the delivery system of step i); and 
 wherein each of (d), (e), and (f) of the re-activator of step ii) is administered by intravenous (i.v.) injection. 
 
     
     
       2. The method of  claim 1 , wherein
 said peptide derived from the antigen-comprising protein has a length of 8, 9 or 10 amino acids, or 
 said peptide derived from the antigen-comprising protein is presented by a MHC-I selected from HLA-A2, HLA-A1, HLA-A3, HLA-B7, HLA-B35, HLA-A24, or HLA-A30. 
 
     
     
       3. The method of  claim 1 , wherein said molecule of (a) is an anti-CLEC9A antibody or antigen-binding fragment thereof, an anti-nectin-like molecule 2 antibody or antigen-binding fragment thereof, or an anti-CD205 antibody or antigen-binding fragment thereof. 
     
     
       4. The method of  claim 1 , wherein the molecule of (a) is an anti-XCR1 antibody or antigen-binding fragment thereof or a chemokine (C motif) ligand 1 (XCL1) or a functionally active variant thereof; and wherein said XCL1 or a functionally active variant thereof comprises or consists of the amino acid sequence of any one of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 10. 
     
     
       5. The method of  claim 1 , wherein
 the antigen-comprising protein of (b) is in a fusion protein with the molecule of (a), or 
 the antigen of the antigen-comprising protein of (b) is an immunogen, a pathogen-derived antigen, or a tumor antigen, or 
 said patient is a human, or 
 said method is for prophylactically treating or treating a tumor and/or an infection. 
 
     
     
       6. The method of  claim 1 , wherein said first adjuvant of (c) and said second adjuvant of (e) are independently selected from the group consisting of a synthetic or recombinant RIG-I agonist, a Toll-like receptor (TLR) ligand, a Montanide, a saponin, a lipopolysaccharide (LPS), and a CpG oligodeoxynucleotide. 
     
     
       7. The method of  claim 6 , wherein said first adjuvant of (c) and said second adjuvant of (e) are independently selected from the RIG-I-agonist and the TLR ligand. 
     
     
       8. The method of  claim 1 , wherein said peptide-loaded MHC-I presenting cell of (d) and the second adjuvant of (e) are administered only once in a time frame of from 5 days to 9 days after the administration of the delivery system of step i). 
     
     
       9. A method of amplifying antigen-specific CD8+ T cells in a patient, wherein the patient has been previously administered an immunogenic composition that activated the CD8+ T cells of the patient against an antigen-comprising protein, wherein the previously administered immunogenic composition does not comprise peptide-loaded MHC-I presenting cells, the method comprising administering to the patient a re-activator comprising:
 (a) primary peptide-loaded major histocompatibility complex class I (MHC-I) presenting cells, wherein the MHC-I presenting cells comprise peripheral blood mononuclear cells (PBMCs) excluding monocyte-derived dendritic cells and wherein the MHC-I presenting cells are obtained from the patient and loaded in vitro with a peptide derived from the antigen-comprising protein prior to administration to the patient;
 (b) an adjuvant which supports a Th-1 mediated response, wherein the adjuvant is a danger signal; and 
 (c) complexed interleukin 2 (IL-2cx), wherein the IL-2cx comprises IL-2 non-covalently bound to an antibody or fragment thereof, wherein the antibody or fragment thereof blocks the binding of IL-2 to the high affinity IL-2 receptor chain (CD25); 
 
 thereby amplifying the activated CD8+ T cells, 
 wherein each of (a), (b), and (c) of the re-activator is administered in a time frame of from 5 days to 12 days after the CD8+ T cells were activated against the antigen, and 
 wherein each of (a), (b), and (c) of the re-activator is administered by intravenous (i.v.) injection. 
 
     
     
       10. The method of  claim 9 , wherein
 said peptide derived from the antigen-comprising protein has a length of 8, 9 or 10 amino acids, or 
 said peptide derived from the antigen-comprising protein is presented by a MHC-I selected from HLA-A2, HLA-A1, HLA-A3, HLA-B7, HLA-B35, HLA-A24, or HLA-A30, or 
 said patient is a human, or 
 said method is for prophylactically treating or treating a tumor or an infection. 
 
     
     
       11. The method of  claim 7 , wherein said TLR ligand is selected from resiquimod (R848), poly ICLC, and polyinosinic:polycytidylic acid (poly I:C). 
     
     
       12. The method of  claim 1 , wherein the peptide loaded MHC-I presenting cells of (d) and the second adjuvant of (e) are administered separately to the patient. 
     
     
       13. The method of  claim 12 , wherein the peptide loaded MHC-I presenting cells of (d) and the second adjuvant of (e) are administered separately to the patient on the same day, and wherein the IL-2cx of (f) is administered to the patient at least one day after the administration of (d) and (e). 
     
     
       14. The method of  claim 13 , wherein the IL-2cx of (f) is administered to the patient one day after the administration of (d) and (e). 
     
     
       15. The method of  claim 13 , wherein the IL-2cx of (f) is administered:
 repeatedly; 
 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 times; 
 every 1 or 2 days; 
 repeatedly during 5 days to 1 month; or 
 for 1 to 2 weeks. 
 
     
     
       16. The method of  claim 9 , wherein the peptide loaded MHC-I presenting cells of (a) and the adjuvant of (b) are administered separately to the patient. 
     
     
       17. The method of  claim 16 , wherein the peptide loaded MHC-I presenting cells of (a) and the adjuvant of (b) are administered separately to the patient on the same day; and wherein the IL-2cx of (c) is administered to the patient at least one day after the administration of (a) and (b). 
     
     
       18. The method of  claim 17 , wherein the IL-2cx of (c) is administered to the patient one day after the administration of (a) and (b). 
     
     
       19. The method of  claim 18 , wherein the IL-2cx of (c) is administered:
 repeatedly; 
 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 times; 
 every 1 or 2 days; 
 repeatedly during 5 days to 1 month; or 
 for 1 to 2 weeks. 
 
     
     
       20. The method of  claim 9 , wherein the CD8+ T cells of the patient have been previously activated against the antigen by administering to the patient the delivery system of  claim 1 , step i). 
     
     
       21. The method of  claim 1 , wherein the peptide-loaded MHC-I presenting cells comprise 1×10 6  to 4×10 8  cells. 
     
     
       22. The method of  claim 9 , wherein the peptide-loaded MHC-I presenting cells comprise 1×10 6  to 4×10 8  cells. 
     
     
       23. The method of  claim 1 , wherein the MHC-I presenting cells are lymphocytes. 
     
     
       24. The method of  claim 23 , wherein the lymphocytes are B cells or T cells. 
     
     
       25. The method of  claim 9 , wherein the MHC-I presenting cells are lymphocytes. 
     
     
       26. The method of  claim 25 , wherein the lymphocytes are B cells or T cells.